Cancer terminator viruses: Unique conditionally replication competent oncolytic viruses producing therapeutic anti-cancer immunomodulating agents.

Cancer terminator viruses (CTVs) are next‑generation conditionally replicating oncolytic adenoviruses that integrate precise tumor targeting, direct oncolysis, and potent cytokine‑mediated immunotherapy into a single platform. In CTVs, viral replication is driven by cancer‑selective promoters such as the progression elevated gene‑3 (PEG‑3) promoter, restricting E1A expression and adenoviral replication to tumor cells while sparing normal tissues. These vectors are "armed" with broad‑acting immunomodulatory cytokines, most notably melanoma differentiation-associated gene‑7/interleukin‑24 (mda‑7/IL‑24) or interferon‑gamma, which can induce cancer‑selective apoptosis, toxic autophagy, anti‑angiogenesis, and robust innate and adaptive immune responses, including "bystander killing" of distant, noninfected tumor cells. Chimeric fiber‑modified backbones such as Ad.5/3 enhance infection of Coxsackie-adenovirus receptor-deficient tumors, broadening applicability to refractory epithelial, prostate, brain, and pancreatic cancers. Preclinical studies demonstrate that CTVs eradicate primary and metastatic lesions in multiple xenograft models and synergize with chemotherapy, radiotherapy, and immune checkpoint inhibitors, especially when combined with advanced delivery technologies such as ultrasound‑targeted microbubble destruction and focused ultrasound double-microbubble platforms for systemic, site‑directed release. Ongoing efforts to incorporate IL‑24 "Superkine," fusion cytokines and fusion Superkines, and rational combinations with immunotherapies position CTVs as a versatile and clinically translatable viro-immunotherapeutic strategy for advanced solid tumors. Progress in these efforts will pave the way for applying these virotherapies for improved cancer treatments in the clinic.